Aseptic processing of cyclosporin A suspensions in a hyaluronic acid media (a hydrogel used as a suspending agent), is complicated by the fact that both the drug and the hyaluronic acid need to be pre-sterilized. Pre-sterilized hyaluronic acid is extremely expensive, costing roughly $1 million dollars for a few kilograms (roughly $10,000 per ounce) of sterile raw material. Additionally, in the process of pre-sterilizing cyclosporin A, the drug is degraded upon irradiation, as shown below and in FIGS. 1 and 2:
TABLE 1Impact of Irradiation on Cyclosporin StabilitySterilizationForm 1 CsAForm 2 CsAForm 3 CsAAmorph, CsAMode(Potency and Imp.)(Potency and Imp.)(Potency and Imp.)(Potency and Imp.)None98.4% w/w94.6% w/w97.7% w/w96.5% w/wTotal Imp: 0.6%Total Imp: 0.6%Total Imp: 0.8%Total Imp: 0.7%15 kGy Gamma93.9% w/w91.8% w/w94.3% w/w92.1% w/w% Rel. Change: 4.5%% Rel. Change: 2.9%% Rel. Change: 3.6%% Rel. Change: 4.6%Total Imp: 1.7%Total Imp: 1.8%Total Imp: 1.3%Total Imp: 1.4%30 kGy Gamma90.7% w/w88.5% w/w91.0% w/w87.7% w/w% Rel. Change: 7.8%% Rel. Change: 6.4%% Rel. Change: 6.9%% Rel. Change: 9.2%Total Imp: 2.8%Total Imp: 2.4%Total Imp: 2.3%Total Imp: 2.3%E-Beam92.6% w/w90.3% w/w93.4% w/w92.0% w/w% Rel. Change: 5.9%% Rel. Change: 4.6%% Rel. Change: 4.5%% Rel. Change: 4.7%Total Imp: 1.5%Total Imp: 1.7%Total Imp: 1.6%Total Imp: 1.3%Cooling the cyclosporin during irradiation does not significantly improve the results, as shown in Table 2, below:
TABLE 2Impact on Cyclosporin Stability after irradiation under Cold ConditionsSterilizationForm 1 CsAForm 2 CsAForm 3 CsAAmorph, CsAMode(Potency and Imp.)(Potency and Imp.)(Potency and Imp.)(Potency and Imp.)None99.4% w/w97.6% w/w98.4% w/w96.5% w/wTotal Imp: 0.7%Total Imp: 0.5%Total Imp: 0.7%Total Imp: 0.7%Cold E-beam94.6% w/w91.1% w/w94.6% w/w92.3% w/w% Rel. Change: 4.8%% Rel. Change: 6.7%% Rel. Change: 3.9%% Rel. Change:Total Imp: 1.5%Total Imp: 1.5%Total Imp: 1.8%4.4%Total Imp: 1.3%Regular E-Beam% Rel. Change: 5.9%% Rel. Change: 4.6%% Rel. Change: 4.5%% Rel. Change:(from PreviousTotal Imp: 1.5%Total Imp: 1.7%Total Imp: 1.6%4.7%Study) % RelativeTotal Imp: 1.3%Change inPotency onSterilizationAdditional levels of degradants need to be qualified in preclinical safety studies. Moreover, a suspension, prepared with only 90-95% of the labeled Cyclosporin A (due to the pre-sterilization process), has a substantial probability of failure to meet regulatory guidelines for shelf-life, since regulatory authorities generally prohibit shelf-lives below 90% of label.
The present invention solves these problems. Disclosed herein are formulations of cyclosporin A, combined with a parenterally-biocompatible suspending agent, which are sterile, exceptionally stable to heat sterilization, and have excellent long-term stability.